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Bone Marrow Transplantation (2006) 38, 1–4
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EDITORIAL
Allogeneic haematopoietic stem cell transplantation for severe autoimmune
diseases: great expectations but controversial evidence
Bone Marrow Transplantation (2006) 38, 1–4.
doi:10.1038/sj.bmt.1705394
Autoimmune diseases (ADs) have been defined as a
‘fascinating but still poorly understood group of diseases’,
which pose ‘some of the most baffling scientific questions
and daunting clinical challenges in internal medicine’.1 This
statement still holds true, and it is generally recognized that
ADs result from three interacting components: genetic,
environmental and regulatory.2,3 In spite of this complexity
and of considerable overlap, there is a tendency to
distinguish ADs with an impaired immune system, also
known as primary ADs, from those that are predominantly
antigen driven.4 There is no better demonstration of the
latter than the clinical studies that have shown the
disappearance of autoantibodies (antithyroid, anti-tissue
transglutaminase) following removal of the antigens (by
thyroidectomy or by gluten-free diet, respectively).5,6 The
proposal that transplantation with genetically engineered
stem cells with the culprit antigen expressed by donorantigen-presenting cells in the thymus might result in
immunological tolerance7 is in accordance with this current
line of thought, which includes the Matzinger ‘danger’
model of autoimmunity.8,9 A different outlook is apparent
for the primary ADs, in which profound abnormalities of
the patients’ immune system are in the foreground.
Systemic lupus erythematosus (SLE) is the most prominent
example of this type of pathogenetic mechanism, where the
intrinsic tendency of B cells to respond excessively to
immune stimulation is thought to be an essential feature of
the disease,10 and causes a veritable ‘autoantibody explosion’.11
Following pioneering experimental studies,12,13 autologous haematopoietic stem cell transplantation (autoSCT)
has now become an accepted therapeutic procedure for
severe ADs, despite the paradox of trying to restore
tolerance by transplanting the patients’ own stem cells.
Extensive reviews have been published, some very recently.14–17 Even if there is still some uncertainty as to
whether genuine tolerance may be really achieved,18,19
disease progression has been clearly shown to be delayed,
especially following high-dose conditioning, albeit with the
drawback of some transplant-related mortality (TRM).20
In order to reduce TRM to a minimum, more specifically
lymphoablative conditioning regimens have been proposed.21 However, in spite of its accepted therapeutic
significance, of the long-term remissions that can be
sometimes achieved22,23 and of the capacity to respond to
treatment again in previously refractory patients, no
authentic cure can be expected.24–26 This is well exemplified
by two patients with coexisting AD and malignant disease
in whom autoSCT was followed by cure of the malignancy
but not of the AD.27,28
The suggestion that allogeneic SCT (alloSCT) might
have a more far-reaching effect was based originally on the
favourable results in patients with AD coexisting with other
diseases.29 A position paper was published recently that
stated that alloSCT was expected to be highly effective for
inducing sustained remissions or ‘cure’ of autoimmune
diseases.30 A series of mechanisms were considered,
including immunomodulation, tolerization by regulatory
T cells and, most importantly, immune-mediated destruction of autoreactive cells.31 By analogy with the multiple
clinical diversifications of immune cellular immunotherapy,32 this last effect was defined as graft-versus-autoimmunity (GVA).33,34 As with the more common and better
known graft-versus-leukaemia effect, also GVA was found
to be more robust when associated with graft-versus-host
disease.35,36
On the other hand, it has been claimed that mixed
chimaerism might be sufficient to keep under control the
autoreactive mechanisms. This is certainly true in experimental autoimmunity, where it has been investigated and
confirmed in numerous laboratories.37–39 However, the
situation is far from being so straightforward in clinical
medicine. Here, along with cases in which post-alloSCT
mixed chimaerism proved effective in controlling the
AD,40,41 there are others in which it was accompanied by
relapse of AD.42,43 The concept that complete remission of
AD depends upon full donor chimaerism has been
validated by the favourable effects of donor lymphocyte
transfusions (DLI) post transplant, designed to obtain full
donor chimaerism.44–46 Unfortunately, there are also cases
in which the AD relapsed in spite of full donor chimaerism.
The first is the now famous patient with rheumatoid
arthritis (RA) in Toronto, who underwent alloSCT from
her HLA-identical brother because of gold-induced aplasia,
and then relapsed with RA 2 years later despite continuing
full donor chimaerism.47 Chimaerism was assessed by
cytogenetics and by tandem repeat-based DNA typing. In
the other case of two concomitant diseases, a patient with
seropositive RA received a nonmyeloablative allogeneic
peripheral blood SCT because of multiple myeloma,
achieved complete remission of both diseases with disappearance of paraprotein and rheumatoid factor (RF), but
relapsed with RA 10 months after transplantation.48 It may
be noted that the HLA-identical brother donor had weak
RF positivity. In addition, peripheral blood transplants are
devoid of mesenchymal cells, which may have a beneficial
effect on AD.49 Perhaps the most informative case of AD
Editorial
2
relapsing in spite of full donor chimaerism has been
recently observed in Genoa. This was a patient with
refractory Evans syndrome who had been transplanted
with bone marrow from his HLA-identical sister in 2000,
and had received five DLIs in order to achieve full donor
chimaerism and complete clinical and haematologic remission.50 However, he had a catastrophic relapse 5 years later.
Full donor chimaerism persisted, and the supernatants of
ex vivo-cultured and expanded B lymphocytes contained
immunoglobulin (Ig)G and IgM that did not react with
the panel of erythrocytes against which the antibodies
eluted from the patient’s Coombs-positive red cells51 were
directed.
The immunologic interpretation of these almost paradoxical relapses in patients with full post transplant donor
chimaerism is still obscure. T cells appear to be involved in
the RA relapses, and it has been hypothesized that residual
recipient cells could sensitize HLA-identical donor T cells
to perpetuate the immunologic imbalance underlying RA.48
However, in a typical B-mediated disease such as Evans
syndrome, a more appropriate interpretation could originate from the notion of long-lived recipient plasma cells,
the contribution of which to long-standing, refractory
humoral autoimmunity has been shown recently.52,53 Shortlived plasma blasts have been shown to become long-lived
plasma cells, occupying postulated survival niches. In NZB/
W mice, a typical model for SLE, long-lived autoreactive
plasma cells have been demonstrated in the bone marrow
and in the spleen.54 However, it is a classical notion that
they can be eradicated following alloSCT, a finding that
was pivotal for the development of stem cell therapy for
autoimmunity in humans.55 An array of cytokines are
necessary for plasma cell survival, such as the well-known
interleukin-6 and also BAFF and APRIL,56 but the most
relevant for plasma cell maintenance has been shown to be
Blimp-1.57 Allotransplantation in lupus mice has been
shown to overcome the disease,12–14 but, in the light of these
observations, one could suspect that a greater degree of
refractoriness may be found in human patients with
systemic autoimmune diseases than suspected previously.
Single case reports, no matter how carefully studied,
cannot provide the final answer but still they should not be
ignored. If it were confirmed that minimal residual
autoimmune disease is capable of surviving the GVA
effects of alloSCT, then the possible advantage of alloSCT
over the safer, although perhaps immunologically less
appealing, autoSCT procedure would inevitably be reduced.
AM Marmont
Division of Haematology and Stem Cell Transplantation
Centre, S Martino’s Hospital, Genoa, Italy
E-mail: [email protected]
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